2-azacycloalkylmethyl substituted vinylene carbinols and ketones

ABSTRACT

Novel derivatives of 2-azacycloalkylmethyl substituted vinylene ketones are described which are useful as anticoagulants.

United States Patent Grisar et a1.

Z-AZACYCLOALKYLMETHYL SUBSTITUTED VINYLENE CARBINOLS AND KETONES Inventors: J. Martin Grisar; George P.

Claxton, both of Cincinnati, Ohio Richardson-Metre" Inc., New York, NY.

Filed: Apr. 25, 1973 Appl. No.: 354,205

Assignee:

US. Cl. 260/240 R, 424/244, 424/264, 424/267 Int. Cl. C07b 29/20, C071) 29/16 Field of Search 260/240 R References Cited UNITED STATES PATENTS 1/1972 Partyka et a1 260/293.8

[111 I 3,853,855 [451 Dec. 10, 1974 Claxton et al., J. Med. Chem. Vol. 15, pages 500 to 503 (1962).

Bolshedvorskaya et a1., Zhur. Organicheskoi Khimii, Vol. 14, pages 1541-1545, (1968).

Primary ExaminerJohn D. Randolph Attorney, Agent, or FirmWi11iam J. Stein; Eugene O. Retter; George W. Rauchfuss, Jr.

[57] ABSTRACT Novel derivatives of 2-azacycl0a1kylmethyl substituted vinylene ketones are described which are useful as anticoagulants.

5 Claims, No Drawings Z-AZACXQLOALKYLMETHYL SUBSTITUTED VINYLENE CARBINOLS AND KETONES FIELD OF THE INVENTION This invention relates to novel 2-azacycloalkylmethyl substituted vinylene ketones, their preparation and to their use in preventing the coagulation of blood.

BACKGROUND OF THE INVENTION pounds which have not previously been described nor reported in literature.

SUMMARY OF THE INVENTION This invention relates to novel 2-azacycloalkylmethyl carbinols and ketones. More particularly, this invention relates to a class of substituted vinylene derivatives which are useful as anticoagulants and which may be represented by the general formula:

Y ll A-CH=CH-C-CH -CH 7 l) wherein m is an integer of from 1 to 3; n is an integer of from 3 to 5; p is an integer of from I to 2; R is hydrogen or a lower alkyl having from 1 to 4 carbon atoms;

R is selected from the group consisting of hydrogen,

lower alkyl having from one to six carbon atoms, lower alkoxy having from one to six carbon atoms, lower alkylthio having from 1 to 6 carbon atoms, halogen, trifluoromethyl and phenyl; Y is the radical or A is selected from the group consisting ofa sigma bond, vinylene and methylvinylene; and the pharmaceutically acceptable acid addition salts thereof.

The compounds of this invention are prepared by heating a solution of a substituted vinylene methyl ketone with magnesium methyl carbonate to form a magnesium chelate and condensing this chelate solution with a l-azacycloalkene in an atmosphere of carbon dioxide. The 2-azacycloalkylmethyl substituted vinylene ketones so prepared are readily reduced to the corresponding alcohols by means of sodium borohydride.

A variety of compositions are also included within the scope of the present invention which are useful as anticoagulants.

DETAILED DESCRIPTION OF THE INVENTION As seen by an examination of Formula (I) above, the compounds of the present invention share in common a 2-azacycloalkylmethyl moiety and a substituted vinylene radical which are attached to the keto or carbinol function of the molecule. The azacycloalkylmethyl moieties'include the 5,6 and 7-membered nitrogen containing saturated heterocyclic rings as defined by the symbol n. Thus, when n is an integer of from 3 to and R is hydrogen, the corresponding heterocycles, lpyrrolidine, piperidine and 2,3,4,5,6,7-hexahydro-lH- azepine, are delineated. These heterocycles may be further substituted as illustrated by the symbol R,, which may represent a lower alkyl group in addition to hydrogen. The term lower alkyl includes members having from 1 to 4 carbon atoms. Illustrative members of this group include the radicals methyl, ethyl, propyl, isopropyl, butyl, sec.-butyl and t-butyl. The Z-azacycloalkyl rings may be either. mono or di-substituted as indicated by the symbol p. When di-substituted, the lower alkyl radicals may be substituted either upon the same carbon atom or upon different carbon atoms. Further substitution in the 2-position, however, is precluded as illustrated by the presence of a hydrogen atom in Formula (I) above. Thus, for example, 6-methyl-2,3,4,5- tetrahydropyridine and Z-phenyI-l-pyrroline were found not to undergo condensation.

The vinylene radical attached to the keto or carbinol function is further substituted in the B-position. The substituents include a terminal phenyl radical, as when the symbol A represents a sigma bond, and an additional unsaturated vinylene and methylvinylene group interjected between the vinylene radical and the terminal phenyl radical. The term methylvinylene includes both the a-methyl and the B-methyl substituted vinylene radicals. The expression sigma bond" is intended to refer to the ordinary single bond linkage between two adjacent carbon atoms, resulting from the overlap of their corresponding orbitals. Thus, when the symbol A represents a sigma bond, the terminal phenyl radical or substituted phenyl radical is linked directly to the vinylene radical attached to the keto or carbinol function of the molecule.

The presence of a phenyl radical is common to all of the compounds of the present invention. This terminal phenyl radical can be either substituted or it may be unsubstituted as indicated by the symbol R Thus when R is hydrogen the terminal phenyl radical remains unsubstituted. In addition the terminal phenyl radical may be mono, di or tri-substituted as indicated by the symbol m. When the terminal phenyl radical is multisubstituted, i.e., the symbol m is an integer of from 2 to 3, the phenyl radical can be indifferently substituted.

That is to say all of the substituents on the phenyl ring neednot be the same. Substitution can take place at any of the available positions of theterminal phenyl ring as is indicated by the nonspecific attachment of the R bond to the center of the ring.

The symbol R includes substituents which are in the nature of aliphatic radicals, aliphatic ethers and aliphatic thioethers. In each case, the aliphatic substituent is a lower alkyl group having from 1 to 6 carbon atoms. In addition to the radicals specifically enumerated for the symbol R, above, these radicals include: pentyl, isopentyl, 3-methylbutyl, hexyl, isohexyl, 3-methylpentyl, 2,3-dimethylbutyl and Z-ethylbutyl. The terminal phenyl radical may also be substituted with 1,2 or 3 halogen atoms. The term halogen" refers only to the fluoro, chloro and bromo radicals. Finally, as indicated in Formula (I) above, the symbol R, represents the specific radicals trifluoromethyl and phenyl.

The compounds of the present invention are Z-azacycloalkylmethyl substituted vinylene ketones when prepared by the novel process of this invention. Reduction of these ketones to the corresponding alcohols, which ganic acid addition salts of the base compounds represented by Formula (I). Illustrative inorganic acids which form suitable salts include hydrochloric, hydrobromic, sulfuric and phosphoric acids as well as acid are also active anticoagulants, is readily achieved using 5 metal salts such as sodium monohydrogen orthophosmethods well known to those skilled in the art. Suitable reducing agents include complex metal hydride reducing agents. Applicants have found sodium borohydride to be the reducing agent of choice in carrying out this phate and potassium hydrogen sulfate. illustrative organic acids which form suitable salts include the mono, di and tricarboxylic acids. Illustrative of such acids are, for example, acetic, propionic, glycolic, lactic, pyruvic,

reduction. Two or more moles of sodium borohydride malonlc, Succlnlc, glutafic fumarlcv mallc tarml'icare generally used per mole of ketone reduced, the additional borohydride serving to neutralize the salts of the 2-azacycloalkylmethyl substituted vinylene ketones to their free base forms. The reaction is conducted in ric, ascorbic, maleic, hydroxymaleic, benzoic, phydroxybenzoic, phenylacetic, cinnamic, salicyclic, 2 phenoxybenzoic and sulfonic acids such as methanesulfonic acid and Z-hydroxyethenesulfonic acid. Either various organic solvents such as methanol, tetrahydrothe mono or the dl'acld Salts can be formed and Such furan or ethyl ether for periods ranging from a few minutes to about 24 hours. In general the reactants are mixed together at temperatures of 0C. or below, whereupon the temperature is gradually allowed to insalts can be utilized in either a hydrated or a substantially anhydrous form.

In general the Z-azacycloalkylmethyl substituted vinylene ketones of the present invention are prepared crease to 30C. Upon completion of the reaction, the by reacting a substituted vinylene methyl ketone with reaction mixture is treated with water and the 2-azacycloalkylmethyl substituted vinylene carbinols are isolated and further purified by crystallization from an appropriate organic solvent.

magnesium methyl carbonate (MMC) in solution to form a magnesium chelate. The resulting chelate is condensed in an atmosphere of carbon dioxide with a l-azacycloalkene or a substituted l-azacycloalkene at The subclass of Z-piperidylmethyl substituted vinylmoderate or ambient temperatures. The 2-azacycloalkene ketones are of particular interest inasmuch as they possess good anticoagulant activity and are readily prepared by condensation of the magnesium chelate with the 2,3,4,5-tetrahydropyridine trimer. This class of ylmethyl substituted vinylene ketones which are formed are isolated as their acid addition salts or as their free base by precipitation or extraction from the reaction mixture. This reaction is schematically reprecompounds is delineated in Formula (1) above wherein 3O sented as follows:

u -A-CH=CH-C-CH3 MMC (mai 0 l zl l l j) ll -A-CH=CH-C-CH2CH 1) \NH P(- wherein the symbols m, n, p, R R and A have the values previously assigned.

The MMC reagent is prepared by the addition of magnesium turnings to dry methanol until all of the l-(2-pip y ln-2- n -(m-m h xyph nyhmetal is converted to magnesium methoxide. A solvent l-(2-piperidyl)-3-buten-2-one, (2-piperidyl)-3-buten-2-one, 4-phenyl-l-(2- pyrrolidinyl)-3-buten-2-one, 4(2,4,6 trimethylphenyl)-l-(Z-pyrrolidinyl)-3-buten-2-one, 4- (p-isopropylphenyl)-l-(2-hexahydro-lH-azepinyl)-3- buten-Z-one, 4-(2,6-dichlorophenyl)-l-(2-piperidyl)- 3-buten-2-one, 4-(3-bromo-4,5-dimethoxyphenyl)-l- (Z-pyrrolidinyl) 3-buten-2-one, 4-(5-bromo-2- methoxyphenyl)-l-(5,5-dimethyl-2-pyrrolidinyl)-3- buten-Z-one, 3,5-hexadien-2-one, 6-(4-hexyloxyphenyl)-l-(6-ethyl- 2-piperidyl)-3,S-hexadien-Z-one, a-[4(butylthio)- styrylI-Z- iperidineethanol, a-[4-phenyl-buta-l ,3- dienyl]-2pyrrolidineethanol, 5,5'dimethyl a-[4- such as dimethylformamide is added and the stirred solution saturated with dry carbon dioxide as described by H. L. Finkbeiner and M. Stiles, J. Am. Chem. Soc, 85, 616 (1963). When a methyl ketone is permitted to 5 react with a large excess of this reagent, a chelate results which is believed to have the formula:

(methylthio)styryll-2-pyrrolidineethanol, and hexahy- 5 Generally, a 2 to 6 molar excess of the MMC reagent dro-a-styryl-2-( l H-azepine )ethanol.

The expression pharmaceutically acceptable acid addition salts" refers to any non-toxic organic or inoris employed at a temperature ranging from to C. Preferably an excess of 4 moles of MMC reagent is used for chelation at the higher temperatures.

The methanol that is formed is removed by sweeping a stream of an inert gas, such as nitrogen, over the hot solution. After a period of time ranging from 2 to 36 hours the chelate solution is permitted to cool and the inert gas is replaced with carbon dioxide. The solution is saturated with carbon dioxide and a carbon dioxide atmosphere is maintained throughout the condensation of the chelate with the l-azacycloalkene.

To the magnesium chelated methyl ketone solution is added a one molar equivalent or slight excess of lazacycloalkene with stirring. In general the condensation is effected by stirring the reaction mixture at ambient temperatures. The preferred reaction solvent is dimethylformamide since the MMC reagent is ordinarily prepared therein. On occasion it may be advantageous to add an additional inert solvent to the reduction mixture if, for example, the reaction is to be conducted at a temperature of less than 6 1C., the freezing point of dimethylformamide. It is further practicable to precipitate the magnesium chelate by the addition of large amounts of ether and to dissolve or suspend the precipitated chelate in other inert solvents. Suitable solvents include tetrahydrofuran, benzene or dimethylacetamide.

Condensation takes place at temperatures ranging from 50 to 100C. Preferably the reaction is conducted at temperatures ranging from 0-60C. both as a matter of convenience and since elevation of the reaction temperature above 100C. results in diminished yields.

The reaction time varies from a few hours to several weeks depending upon the reaction temperature and the nature of the reactants, particularly with respect to the degree of steric hindrance of the substituted vinylene methyl ketone (II). Inasmuch as the reaction is conducted and remains a homogeneous solution until completion, the duration of the reaction can readily be extended for several weeks. Preferably the reaction is conducted in a period of from 16 to 60 hours.

Of particular importance to the successful operation of this reaction is the maintenance of an appropriate atmosphere. Some success is obtained under normal atmospheric conditions, particularly in the presence of a small amount of moisture. Under anhydrous conditions in an atmosphere of nitrogen, however, no product is obtained. Consistently good yields result when the condensation is carried out in an atmosphere of carbon dioxide.

The desired products of this invention are isolated by pouring the reaction mixture into an excess of dilute acid. Preferably a mixture of 2 to 12 normal hydrochloric acid and ice is employed. When the acid addition salt of the desired 2-azacycloalkylmethyl ketone precipitates, it is collected by filtration. Alternatively, the acidified reaction mixture is extracted with a suitable solvent, as for example, chloroform or methylene chloride, and the solvent extract evaporated, leaving the desired product as a residue. It is also possible, but generally more cumbersome, to treat the acidified reaction mixture with a base such as sodium hydroxide until al kaline. The desired product can then be extracted using an appropriate solvent from the alkaline slurry containing precipitated magnesium hydroxide. In either event the crude products are readily purified by recrystallization of their acid addition salts using ordinary solvents or solvent mixtures.

It is important to note that the l-azacycloalkenes can exist as trimers, as for example, the trimers of 1-;

pyrroline and 2,3,4,5-tetrahydropyridine. In the case of the latter compound it can, exist in two isomeric forms that are known as a and B-tripiperidein. In solution these trimers readily depolymerize to their monomers in a manner similar to the well known behavior of formaldehyde. However, under alkaline aqueous conditions 2,3,4,5-tetrahydropyridine undergoes an irreversible self-condensation to form 'y-tripiperidein. This self-condensation does not occur using the process of the present invention.

Illustrative l-azacycloalkenes as indicated in Formula (III) above which are useful in the instant process include: l-pyrroline, 3-methyll-pyrroline. 5 ,S-dimethyll pyrroline, 3-propyl-2,3 ,4,5- tetrahydropyridine, 4-t.-butyl-2,3,4,5- tetrahydropyridine, 3,5-diethyl-2,3,4,5- tetrahydropyridine, 3,4,5 ,6-tetrahydro-2H-azepine,

and 2,2-dimethyl-3,4,5,6-tetrahydro-2l-I-azepine.

The substituted vinylene methyl ketones employed herein as starting materials are prepared using the well known procedure of condensing acetone with a substituted benzaldehyde or cinnamaldehyde in the presence ofa base. This reaction, which is known as the Claisen- Schmidt condensation, involves the preparation of unsaturated ketones by an aldol type condensation of aromatic aldehydes with acetone followed by a loss of water. This reaction is generally conducted in an aqueous medium using either sodium hydroxide or potassium hydroxide as a base. The resulting double bond or double bonds are usually obtained in the trans form. The stereochemistry concerned with the double bonds remains generally unaffected by the reactions which lead to the compounds of the present invention.

The compounds of the present invention, including their acid addition salts and isomers, are useful as anticoagulants. They affect th coagulation of blood by preventing the aggregation of blood platelets. The blood platelets play a dominant role in thrombotic conditions, both in the initial event and at the occlusive stage. Arterial thrombosis, particularly in arteries supplying the heart muscle and brain, is a leading cause of death and disability. The compounds of the present invention can be administered to animals, mammals and humans, either per se or in combination with conventional pharmaceutical carriers in dosage unit forms. Suitable dosage unit forms include oral preparations such as tablets, capsules, powders, granules, oral solutions and suspensions, sublingual and intrabuccal preparations, as well as parenteral dosage unit forms which are useful for subcutaneous, intramuscular or intravenous administration. The quantity of active ingredient administered can vary over a wide range so as to provide from about 1.0 mg/kg to about mg/kg of body weight per day in order to achieve the desired effect. Each unit dose can contain from about 5 to 500 mg of the active ingredient in combination with the pharmaceutical carrier. Such doses may be administered from 1 to 4 times daily.

In preparing solid compositions such as tablets, the principal active ingredient is mixed with conventional pharmaceutical excipients such as gelatin, starches, lactose, magnesium stearate, talc, acacia, dicalcium phosphate and functionally similar materials. Tablets can be laminated, coated or otherwise compounded to provide for a prolonged or delayed action and to release a predetermined succesive amount of medication. Capsules are prepared by mixing the active ingredient with an inert pharmaceutical filler or diluent and filled in either hard gelatin capsules or machine encapsulated soft gelatin capsules. Syrups or elixirs can contain the active ingredients together with sucrose or other sweetening agents, methyl and propyl parabens as preservatives, and suitable coloring and flavoring agents.

Parenteral fluid dosage forms are prepared by utilizing the active ingredient in a sterile liquid vehicle, the preferred vehicle being water of a saline solution. Compositions having the desired clarity, stability and adaptability for parenteral use are obtained by dissolving from about 0.1 mg to about 3 grams of the active ingredient in a vehicle consisting of a mixture of nonvolatile liquid polyethylene glycols which are soluble in both water and organic liquids, and which have molecular weights ranging from about 200 to about 1,500. Such solutions may advantageously contain suspending agents, such as sodium carboxymethylcellulose, meth-- ylcellulose, polyvinylpyrrolidone or polyvinyl alcohol. Additionally, they may contain bactericidal and fungicidal agents, as for example, parabens, benzyl alcohol, phenol or thimerosal. If desired, isotonic agents can be included, such as sugar or sodium chloride, as well as local anesthetics, stabilizing or buffering agents. in order to further enhance stability, the parenteral compositions may be frozen after filling and water removed by freeze-drying techniques well known in the art, enabling such dry, lypohilized powders to be reconstituted immediately prior to their use.

The following preparations and examples are illustrative of the novel compounds of the present invention and their compositions, but are not to be constructed as necessarily limiting the scope thereof.

EXAMPLE I 2,3,4,5-Tetrahydropyridine Trimer To 170 g (2.0 moles) of piperidine is added 120 g (2.0 moles) of acetic acid via dropwise addition at a' temperature below 10C. The resulting solution is added dropwise over a period of l hour to an aqueous solution containing 2.2 moles of Ca(ClO) while maintaining the temperature of the reaction mixture at to -C. Stirring is continued for an additional minutes, and the mixture is extracted with ether. The ether extracts are combined, dried over anhydrous Na SO and most of the solvent removed. (Caution! N- chloropiperidine tends to decompose spontaneously.) Approximately 200 ml of ether is permitted to remain and temperatures in excess of 60C. are avoided. The remaining ether solution is added over a period of 2.5 hours in dropwise fashion to a vigorously stirred, refluxing solution containing 265 g (4.0 moles) of potassium hydroxide in 1,250 ml of anhydrous ethyl alcohol. Stirring is continued for 2 hours and the mixture is allowed to remain at room temperature during which the 2,3,4,5-tetrahydropyridine trimerizes. The potassium chloride which precipitates is removed by filtration, washed with anhydrous ethanol, and the ethanol removed from the filtrate by distillation. The residue is dissolved in 750 ml of water, the potassium chloride previously collected is added, and the solution extracted with ether. The combined ether extracts are dried (MgSO and the solvent removed by evaporation. Recrystallization of the residue from acetone yields 2,3,4,S-tetrahydropyridine as the a-trimer hav ing a M.P. of58-6lC. The B-isomer (M.P. 4068C.) can be converted to the more stable a-isomer by recrystallization from acetone containing 2 percent water. The material so prepared is stored in a closed container over potassium hydroxide and is stable for over one year.

EXAMPLE u l-Pyrroline Trimer To 140.3 g (1.05 moles) of N-chlorosuccinimide is added a solution of 71.1 g (1 mole) of pyrrolidine dissolved in l l of ethyl ether. The mixture is stirred at room temperature under N for 24 hours and sufficient water added to dissolve the solids. The ether phase is separated, dried over anhydrous sodium sulfate and the solvent evaporated under nitrogen. (Caution! N- chloropyrrolidine tends to decompose spontaneously.) Approximately ml of ether are permitted to remain and temperatures in excess of 60C. are avoided. The remaining ether solution is added over a period of 1 A hours in dropwise fashion to a vigorously stirred, icecooled solution of 2 N methanolic potassium hydroxide. Stirring is continued for 1 hour and the methanol removed at a temperature of 2530C. at a reduced pressure of approximately 200 mm. Water is added to the remaining residue and the resulting mixture is subjected to continuous extraction with ethyl ether. The ether extract is separated and distilled under nitrogen at atmospheric pressure. Fractions having a B.P. 8190C. and 9197C. were collected, the latter fraction warming spontaneously, presumably due to exothermic trimerization. Both fractions are capable of condensation with MMC chelates of methyl ketones.

EXAMPLE lll Trans-4-(4-methoxyphenyl)-l-(2-piperidyl)-3-buten- 2-one To 430 g of a solution of magnesium methyl carbonate in dimethylformamide (1 mole), which is heated to C. under an atmosphere of carbon dioxide, is added 44.1 g (0.25 mole) of trans-4-(4- methoxyphenyl)-3-buten-2-one. The mixture is stirred at 120C. for 4 hours under a stream of nitrogen while permitting the methanol that forms to escape. The mixture is allowed to cool under an atmosphere of carbon dioxide and 25.5 g (0.30 mole) of 2,3,45- tetrahydropyridine (as a-tripiperidein) is added and stirring continued at room temperature under an atmosphere of carbon dioxide for a period of 70 hours. The reaction mixture is poured into a mixture of 300 ml of concentrated HCl and 700 g of ice and extracted with methylene dichloride. The extracts are combined, dried over anhydrous sodium sulfate, and the solvent removed. The crude trans-4-(4-methoxyphenyl)-l-(2- piperidyU-3-buten-2-one is obtained as the hydrochloride salt and when twice recrystallized from isopropyl alcohol has a MP. of 188-9C.

EXAMPLE 1V Trans-4-(4-methoxyphenyl)-l-(pyrrol-2-yl)-3-buten- 2one Following essentially the same procedure as described in the preceding Example, but substituting the trimer of l-pyrroline for the 2,3, 1,5- tetrahydropyridine, results in the formation of trans-4- (4-methoxyphenyl)-1-(pyrrol-2-yl)-3-buten-2-one as the hydrochloride salt.

EXAMPLE V Trans-4-phenyll -(2-piperidyl}-3-buten-2-one Following essentially the same procedure as described in Example 111 above, but substituting trans-4-phenyl-3-buten-2-one for the trans-4-(4- methoxyphenyl)-3-buten-2-one above, results in the preparation of trans-4-phenyl-1-(2-piperidyl)-3-buten- 2-one as the hydrochloride salt, which when recrystallized from isopropyl alcohol has a M.P. of l83-5C.

EXAMPLE v1 EXAMPLE VII Trans-4-(4-butoxyphenyl)-l-(2-piperidyl)-3-buten- 2-one Following essentially the same procedure as described in Example In above, but substituting trans-4- (4-butoxyphenyl)-3-buten-2-one for the trans-4-(4- methoxyphenyl)-3-buten-2-one above, results in the preparation of trans-4-(4-butoxyphenyl)-l-(2- piperidyl)-3-buten-2-one as the hydrochloride salt,

which when recrystallized from isopropyl alcohol has a M.P. of l724C.

EXAMPLE Vlll l-( 2-Piperidyl )-4-( 3 ,4,5-trimethoxyphenyl )-3-buten- 2-one Following essentially the same procedure as described in Example 1]! above, but substituting 4-(3,4,5- trimeth'oxyphenyl)ii-buten-Z-one for the trans-4-(4- methoxyphenyl)-3-buten-2-one above, results in the preparation of l-(2-piperidyl)-4-(3,4,5-

' (trimethoxyphenyl)-3-buten-2-one as the hydrochloride salt, which when recrystallized from isopropyl alcohol has a M.P. of 23l-2C. (dec.)

EXAMPLE IX 4-( 4-Biphenylyl)- l 2-piperidyl )-3-buten-2-one Following essentially the same procedure as described in Example Ill above, but substituting 4-(4- biphenylyl)-3-buten-2-one for the trans-4-(4- methoxyphenyl)-3-buten-2-one above, results in the preparation of 4-(4-biphenylyl)-l-(2-piperidyl)-3- buten-Z-one as the hydrochloride salt, which when recrystallized from isopropyl alcohol has a M.P. of 2l0-l2C.

EXAMPLE X 6-( 3 ,4-Dimethoxyphenyl l 2-piperidyl )-3,5-

hexadien-2-one Following essentially the same procedure as described in Example 11] above, but substituting 6-(3,4- dimethoxyphenyl)-3,5-hexadien-2-one for the trans-4- (4-methoxyphenyl)-3-buten-2-one above, results in the preparation of 6-(3,4-dimethoxyphenyl)-l-(2- piperidyl)-3,5-hexadien-2-one as the hydrochloride salt, which when recrystallized from isopropyl alcohol has a M.P. of l93-5C.

EXAMPLE XI -Methyl-6-phenyll Z-piperidyl )-3 ,5-hexadien-2-one Magnesium methyl carbonate (1.2 moles, 2 N in dimethylformamide) is heated to 120C. under an atmosphere of carbon dioxide. The compound 5-methyl-6- phenyl-3,5-hexadien-2'one. 53.0 g (0.285 mole) is added and the mixture is stirred at 120C. for a period of 4 hours under a stream of nitrogen while permitting the methanol that forms to escape. The mixture is allowed to cool under an atmosphere of carbon dioxide and 57.0 g (0.68 mole) of 2,3,4,5-tetrahydropyridine (as a-tripiperidein) is added and stirred at room temperature under an atmosphere of carbon dioxide for a period of hours. The reaction mixture is poured into a concentrated HCl-ice mixture and extracted with methylene dichloride. The extracts are combined, washed with water, dried over anhydrous sodium sulfate, and the solvent removed. The crude 5-methyl-6- phenyl-l-(2-piperidyl)-3,5-hexadien-2-one which remains is recrystallized twice from isopropyl alcohol as the hydrochloride salt and is obtained in 48 percent yield (41.6 g) and has a M.P. of l79-80C.

EXAMPLE XII 6-Phenyll 2-piperidyl)-3,5-hexadien-2-one Following essentially the same procedure as described in Example In above, but substituting 6-phenyl-3,5-hexadien-2-one for the trans-4-(4- methoxyphenyl)-3-buten-2-one above, results in the preparation of 6-phenyl-l-(2-piperidyl)-3,5-hexadien- 2-one as the hydrochloride salt, which when recrystallized from isopropyl alcohol has a M.P. of l70-80C.

EXAMPLE Xlll 4-[ (4-Methylthio)phenyl]- l Z-piperidyl )-3-buten- 2 one EXAMPLE XIV 4-[(4-Methylthio )phenylll pyrrol-2-yl )-3-buten- 2-one Following essentially the same procedure as described in the preceding Example, but substituting the trimer of l-pyrroline for the 2,3,4,5- tetrahydropyridine, results in the formation of 4-[(4- methylthio)phenyl]-l-(pyrrol-2-yl)-3-buten-2-one as the hydrochloride salt.

EXAMPLE XV trans, trans-a-( 3-Methyl-4-phenyl-l ,3-butadienl -yl)-2- piperidineethanol fumarate (2: l

To a suspension of 3.7 g (0.098 mole) of sodium borohydride in 200 ml of absolute ethanol is slowly added over a period of 30 minutes of 10.0 g (0.033 mole of 5-methyl-6-phenyl-l-(Z-piperidyl)-3,5-hexadien-2-one hydrochloride. The resulting mixture is stirred overnight at room temperature and poured into 800 ml of water. The product is extracted from the diluted reaction mixture with ether, and the ether extract is washed with 3 portions of a l0 percent aqueous acetic acid solution. The acid washes are combined and made alkaline using a 2 N sodium hydroxide solution. The product is re-extracted into ether, the extracts combined, dried over anhydrous sodium sulfate and the solvent removed by evaporation. The residue is dissolved in isopropanol, and a solution of 4.0 g (0.035 mole) of fumaric acid in isopropanol is added. The product crysvmg tallizes as the fumarate salt and is recrystallized from an isopropanol solution containing a small amount of water. The desired trans, trans-a-(3-methyl-4-phenyl-1,3- butadien-l-yl)-2-piperidineethanol fumarate (2:1) is a mixture of diastereoisomers having a M.P. 161 -l 74C. and an ultraviolet absorption of y 274 nm (e 56,700).

Following essentially the same procedure but substituting for the 5-methyl-6-phenyl-l-(2-piperidyl)-3,5- hexadien-Z-one hydrochloride above, the following ketone hydrochlorides: 4-[(4-methylthio)phenyl]-1-2- piperidyl)-3-buten-2-one, 6-phenyl-l-(2-piperidyl)- 3,5-hexadien-2-one, trans-4-phenyl-l-(2-piperidyl)-3- buten-2-one and trans-4-(4-methoxyphenyl)-1-(2- piperidyl)-3-buten-2-one, results in the formation of the following compounds respectively: trans-a-[4- (methylthio)styryl1-2-piperidineethanol fumarate (21I), having a M.P. of l78-84C. (dec.), a-(4- phenylbuta-l,3-dien-l-yl)-2-piperidineethanol fumarate (2:1 having a M.P. of l68-70C. (dec.). trans-astyryl-Z-piperidineethanol fumarate (2:1), having a M.P. of l748C. (dec.) and trans-a-(4-methoxystyryl)-2-piperidineethanol fumarate (2:1), having a M.P. of l4850C. (dec.)

EXAMPLE XVI The anticoagulant activity of the compounds of this invention is determined by the inhibition of platelet (white thrombus) aggregation. which is the initial phase involved in the coagulation of blood. Plateletrich plasma (PRP) obtained from a human volunteer, having a platelet count of approximately 400,000/mm is aggregated using approximately 2 micrograms of adenosine diphosphate per ml of PRP. Quantitative platelet aggregation measurements are made using a photometer connected to an automatic recorder which measures the changes in optical clarity of a standard cell containing the test solution. As the platelets aggregate, light transmission increases and thus both the rate of aggregation and the degree of aggregation can be determined. In this fashion, adenosine diphosphate induced aggregation of platelet-rich plasma is compared under identical circumstances to a corresponding aliquot containing a dilute solution of the test compound. The results are expressed as a percent inhibition.

Following this procedure the compound 4-[(4- methylthio)phenyl]-l-(2piperidyl)-3-buten-2-one hydrochloride at a concentration of IO and 3 micrograms/milliliter demonstrates an in vitro inhibition of adenosine diphosphate induced platelet aggregation in human platelet-rich plasma of 43 percent and 22 percent, respectively.

EXAMPLE XVII Preparation of a tablet formulation One thousand tablets for oral use, each containing 25 of 4-[(4-methylthio)phenyl]-l-(2-piperidyl)-3- buten-2-one hydrochloride are prepared according to the following formulation:

The 4-H4-methylthio)phenyl]-l-(2-piperidyl)-3- buten-Z-one hydrochloride and dicalcium phosphate are mixed well, granulated with a 7.5 percent aqueous solution of methylcellulose, passed through a No. 8 screen and carefully dried. The dried granules are passed through a No. 12 screen, blended with talc and calcium stearate and compressed into tablets.

EXAMPLE XVIII Preparation of a capsule formulation One thousand two-piece hard gelatin capsules for oral use each containing 100 mg of 4-H4 methylthio)phenyl]-l-(2-piperidyl)-3-buten-2-one hydrochloride are prepared from the following ingredients:

Grams (a) 4-l(4 methylthio)phenyl]-l-(Z- piperidyl)3buten-2 one hydrochloride lUU (b) Lactose. U.S.P. Hi0 (c1 Starch. USP lo (d1 Talc. USP. 5

EXAMPLE XIX Preparation of a parenteral solution A sterile aqueous suspension suitable for parenteral use is prepared from the following ingredients:

Grams (a) 4-K(4-methylthiolphenyl]-l-(Z- piperidyl)-3-huten-2-one hydrochloride 1 (b) Polyethylene glycol 4000. U.S.P 3 (c) Sodium chloride 0.) (d) Polyoxyethylene derivatives of star hitan monooleate (TWEEN U.S.P. 0.4 (e) Sodium metabisulfite 0.1 (f) Methylparaben, U.S.P 0. l8 (g) Propylparaben. U.S.P. 0.02 (h) Water for injection qs to I00 ml The parabens, sodium metabisulfite, and sodium chloride are dissolved in approximately one-half the volume of water for injection at 80C. with stirring. The solution is cooled to below 40C. and the active ingredient is dissolved therein followed by the polyethylene glycol 4,000 and the polyoxyethylene derivatives of sorbitan monooleate. The cooled solution is adjusted to the final volume with water for injection and is then sterilized by sterile filtration through a suitable filter. Each one ml of solution contains 10 mg of 4-[(4- methylthio)phenyl]-l-(2-piperidyl)-3-buten-2-one hydrochloride as the active ingredient.

We claim:

1. A 2-azacycloalkylmethyl substituted vinylene carbinol and ketone having the formula:

A is selected from the group consisting of a sigma bond, vinylene and methylvinylene; and the pharmaceutically acceptable acid addition salts thereof.

2. A compound of claim 1 wherein n is 4; R is hydrogen; and Y is the radical =0.

3. A compound of claim 1 which is 4-[(4- methylthio)phenyl]- l -(2-piperidyl)-3-buten-2-one and its pharmaceutically acceptable acid addition salts.

4. A compound of claim 1 which is 4-(4-tertbutylphenyl)-1-(Z-piperidyl)-3-buten-2-one and its pharmaceutically acceptable acid addition salts.

5. A compound of claim 1 which is 4-(4- butoxyphenyl)-l-(Z-piperidyl)-3-buten-2-one and its pharmaceutically acceptable acid addition salts 

1. A 2-AZACYCLOALKYLMETHYL SUBSITUTED VINYLENE CARBINOL AND KETONE HAVING THE FORMULA:
 2. A compound of claim 1 wherein n is 4; R1 is hydrogen; and Y is the radical O.
 3. A compound of claim 1 which is 4-((4-methylthio)phenyl)-1-(2-piperidyl)-3-buten-2-one and its pharmaceutically acceptable acid addition salts.
 4. A compound of claim 1 which is 4-(4-tert-butylphenyl)-1-(2-piperidyl)-3-buten-2-one and its pharmaceutically acceptable acid addition salts.
 5. A compound of claim 1 which is 4-(4-butoxyphenyl)-1-(2-piperidyl)-3-buten-2-one and its pharmaceutically acceptable acid addition salts. 